Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth

Chunyong Ding; Mengyan Du; Zhi Xiong; Xue Wang; Hongji Li; Ende He; Han Li; Yijing Dang; Qing Lu; Shicong Li; Ruoxuan Xiao; Zhiai Xu; Lili Jing; Liufu Deng; Xiyuan Wang; Meiyu Geng; Zuoquan Xie; Ao Zhang

doi:10.1039/D3SC01896B

Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth†

Chunyong Ding,

‡*^ag Mengyan Du,‡^bef Zhi Xiong,‡^ad Xue Wang,‡^a Hongji Li,^a Ende He,^a Han Li,^bf Yijing Dang,

^c Qing Lu,^a Shicong Li,^a Ruoxuan Xiao,^a Zhiai Xu,

^c Lili Jing,*^a Liufu Deng,^a Xiyuan Wang,

^b Meiyu Geng,^be Zuoquan Xie*^be and Ao Zhang*^a

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* Corresponding authors

^a Shanghai Frontiers Science Center of Drug Target Identification and Delivery, College of Pharmaceutical Sciences, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China
E-mail: chunding@sjtu.edu.cn, lilijing@sjtu.edu.cn, ao6919zhang@sjtu.edu.cn
Tel: +86 21 50806035

^b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
E-mail: zqxie@simm.ac.cn

^c School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China

^d School of Pharmacy, Nanchang University, Jiangxi 330000, China

^e University of Chinese Academy of Sciences, Beijing, China

^f School of Life Science and Technology, ShanghaiTech University, Shanghai, China

^g Zhangjiang Institute of Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China

Abstract

Controllable activation of the innate immune adapter protein – stimulator of interferon genes (STING) pathway is a critical challenge for the clinical development of STING agonists due to the potential “on-target off-tumor” toxicity caused by systematic activation of STING. Herein, we designed and synthesized a photo-caged STING agonist 2 with a tumor cell-targeting carbonic anhydrase inhibitor warhead, which could be readily uncaged by blue light to release the active STING agonist leading to remarkable activation of STING signaling. Furthermore, compound 2 was found to preferentially target tumor cells, stimulate the STING signaling in zebrafish embryo upon photo-uncaging and to induce proliferation of macrophages and upregulation of the mRNA expression of STING as well as its downstream NF-kB and cytokines, thus leading to significant suppression of tumor cell growth in a photo-dependent manner with reduced systemic toxicity. This photo-caged agonist not only provides a powerful tool to precisely trigger STING signalling, but also represents a novel controllable STING activation strategy for safer cancer immunotherapy.

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Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth†

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Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth

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